Alnylam Advances Zilebesiran Into Global Phase 3 Cardiovascular Outcomes Trial Following Promising Phase 2 KARDIA Results
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a recognized leader in RNA interference (RNAi) therapeutics, announced a major milestone in its cardiovascular pipeline: the decision to move zilebesiran into a global Phase 3 cardiovascular outcomes trial (CVOT). The investigational therapy, a subcutaneously administered RNAi therapeutic targeting angiotensinogen (AGT), is being developed to reduce the risk of major adverse cardiovascular events (MACE) by offering a novel and durable approach to blood pressure management.
This decision, announced during the European Society of Cardiology (ESC) Congress 2025 in Madrid, Spain, follows a growing body of evidence generated from the company’s comprehensive Phase 2 KARDIA program. Data from the most recent study, KARDIA-3, presented as a late-breaking abstract at the conference, reinforced zilebesiran’s potential to transform the treatment paradigm for patients with uncontrolled hypertension and high cardiovascular risk.
The global Phase 3 trial, to be called ZENITH (ZilebEsiraN CardIovascular OuTcome Study in Hypertension), is expected to enroll approximately 11,000 patients across more than 30 countries. Alnylam, in partnership with Roche, aims to initiate this large-scale trial by the end of 2025, pending regulatory approvals.
Hypertension: A Persistent Global Health Crisis
Hypertension, often referred to as the “silent killer,” is one of the most prevalent chronic conditions worldwide. It affects an estimated 1.3 billion people globally, with more than half of patients either untreated or inadequately controlled despite available therapies. Elevated blood pressure is a leading modifiable risk factor for cardiovascular disease (CVD), which remains the number one cause of death worldwide.
Even modest reductions in systolic blood pressure (SBP) are associated with significant decreases in cardiovascular risk. Clinical data consistently show that lowering SBP by as little as 5 mmHg can reduce the risk of major adverse cardiovascular events—including myocardial infarction, stroke, and cardiovascular death—by up to 10–15%.
Despite the widespread availability of antihypertensives, many patients remain at high risk due to poor adherence, drug resistance, or the limitations of existing therapies. This unmet need underscores the importance of innovative treatment approaches such as zilebesiran, which leverages RNAi technology to provide long-lasting suppression of AGT, the precursor protein that fuels the Renin-Angiotensin-Aldosterone System (RAAS).
Zilebesiran: A Novel RNAi-Based Antihypertensive
Alnylam Zilebesiran is designed to target liver-expressed angiotensinogen (AGT), the most upstream precursor of the RAAS pathway. By silencing AGT production at the genetic level, zilebesiran aims to disrupt the cascade that regulates vascular tone, fluid balance, and blood pressure.
Unlike conventional RAAS inhibitors such as ACE inhibitors or angiotensin receptor blockers (ARBs), which act downstream and often require daily dosing, Alnylam zilebesiran is administered as a subcutaneous injection every six months. This durable profile has the potential to dramatically improve adherence, reduce pill burden, and provide more consistent blood pressure control over time.
Insights from the KARDIA Phase 2 Program
The KARDIA clinical development program has been central to evaluating zilebesiran’s safety, efficacy, and dosing strategy. The program includes three Phase 2 trials—KARDIA-1, KARDIA-2, and KARDIA-3—each designed to examine different patient populations and treatment contexts.
- KARDIA-1 tested zilebesiran as monotherapy in patients with mild-to-moderate hypertension.
- KARDIA-2 evaluated zilebesiran in combination with standard antihypertensives, including ACE inhibitors, ARBs, and calcium channel blockers.
- KARDIA-3, the most recent study, targeted patients with uncontrolled hypertension and high cardiovascular risk despite treatment with two or more background antihypertensives.
Across these studies, zilebesiran Alnylam consistently demonstrated meaningful reductions in both office and ambulatory SBP, along with a favorable safety and tolerability profile.
KARDIA-3 Results: Supporting the Path to Phase 3
The KARDIA-3 trial was specifically designed to inform the patient population, dosing regimen, and study design of the upcoming Phase 3 ZENITH trial.
Study Design and Population
- Enrolled patients had uncontrolled hypertension and were already receiving at least two antihypertensive medications, including a diuretic.
- The study population was high-risk, with many participants having established cardiovascular disease or multiple comorbidities.
- Patients were randomized to receive zilebesiran at 300 mg or 600 mg or placebo.
Efficacy Findings
- At Month 3, a single 300 mg dose of zilebesiran achieved a placebo-adjusted reduction of -5.0 mmHg in office SBP (p=0.0431).
- At Month 6, this effect was sustained, with a reduction of -3.9 mmHg (95% CI: -8.5, 0.7).
- Interestingly, the higher 600 mg dose did not demonstrate incremental benefit, highlighting 300 mg as the optimal dose for further development.
Although the study narrowly missed its stringent statistical threshold for significance due to multiplicity adjustments, the observed blood pressure reductions were clinically meaningful and aligned with prior findings.
Enhanced Effects in Specific Subgroups
A particularly compelling signal was seen in patients with baseline SBP ≥140 mmHg who were taking a diuretic plus another antihypertensive. In this Alnylam subgroup, zilebesiran produced reductions of ≥8 mmHg, sustained for six months. This supports the synergistic benefit of combining zilebesiran with diuretic therapy, as observed in KARDIA-2.
Biomarker Improvements
Zilebesiran also demonstrated favorable effects on cardiac and renal biomarkers, including reductions in NT-proBNP and urinary albumin-to-creatinine ratio (UACR). Alnylam These findings suggest potential long-term benefits beyond blood pressure control, possibly reducing the risk of heart failure and chronic kidney disease progression.
Safety Profile
- Zilebesiran was generally well tolerated across treatment arms.
- Adverse events were mostly mild-to-moderate, non-serious, and transient.
- Rates of hyperkalemia, kidney dysfunction, and hypotension were low.
- Serious adverse events occurred in 3.8% of zilebesiran patients vs. 4.5% in placebo, with no deaths reported during the six-month double-blind period.
Expert Perspectives
Alnylam Leadership
“Cardiovascular disease, largely driven by uncontrolled hypertension, is a global health crisis and remains the leading addressable cause of Alnylam cardiovascular morbidity and mortality,” said Pushkal Garg, M.D., Chief Research and Development Officer at Alnylam.
“The KARDIA-3 results demonstrate that a single dose of zilebesiran provided continuous control of blood pressure over the 24-hour period, day and night, for up to six months, while also showing the potential to improve cardiac and renal biomarkers independent of blood pressure reduction. Taken together with the full KARDIA Phase 2 program data, these findings reinforce that targeting angiotensinogen – the most upstream precursor of the RAAS – with zilebesiran offers a differentiated approach that has the potential to improve blood pressure control and cardiovascular outcomes.”
Clinical Investigators
Neha Pagidipati, M.D., MPH, FACC, Associate Professor of Medicine, Cardiology, at Duke Clinical Research Institute, and the lead investigator of KARDIA-3, highlighted the clinical implications:
“Patients with uncontrolled hypertension despite the use of multiple background therapies are at the highest risk of major adverse cardiovascular events. It is well known that reductions in systolic blood pressure of five mmHg or more can result in a reduction in cardiovascular risk. Therefore, I’m excited by the KARDIA-3 results, which together with the additional Phase 2 data from the KARDIA program, support zilebesiran’s potential to achieve clinically meaningful, sustained blood pressure reductions in high-risk patients. This, in turn, may lead to more consistent long-term blood pressure control and improved cardiovascular outcomes.”
ZENITH Phase 3 Trial: A Landmark CVOT
The upcoming ZENITH trial will be one of the largest and most ambitious CVOTs in hypertension to date.
- Enrollment: Approximately 11,000 patients.
- Population: Patients with uncontrolled hypertension on two or more standard antihypertensives (one being a diuretic), with either established CVD or high CV risk.
- Design: Randomized, double-blind, placebo-controlled.
- Intervention: Zilebesiran 300 mg administered every six months.
- Primary Endpoint: Composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or heart failure events (hospitalization or urgent visit).
- Timeline: Trial initiation targeted for end of 2025.
By focusing on hard cardiovascular outcomes rather than surrogate endpoints, ZENITH is designed to definitively establish zilebesiran’s role in reducing morbidity and mortality in high-risk patients.
Broader Implications for Alnylam and Roche
Alnylam’s advancement of zilebesiran into Phase 3 is strategically significant for several reasons:
- Pipeline Expansion Beyond Rare Diseases
Alnylam is best known for pioneering RNAi therapies in rare genetic disorders such as hATTR amyloidosis and acute hepatic porphyria. With zilebesiran, the company is expanding into common, high-prevalence conditions like hypertension, potentially opening a much larger commercial market. - Partnership with Roche
Roche brings global scale, regulatory expertise, and cardiovascular drug development experience. Their collaboration is expected to accelerate the clinical and commercial path forward for zilebesiran. - First-in-Class Potential
If successful, zilebesiran could become the first RNAi therapy approved for hypertension, establishing RNAi as a viable platform in cardiometabolic disease.
The journey of zilebesiran from Phase 2 to Phase 3 reflects both scientific innovation and strategic foresight. By targeting AGT upstream in the RAAS cascade, zilebesiran has the potential not only to improve blood pressure control but also to meaningfully reduce the burden of cardiovascular disease worldwide.
The next several years will be critical. With ZENITH set to enroll tens of thousands of patients and generate outcome data across multiple geographies, the trial will serve as a landmark test for RNAi therapeutics in widespread chronic conditions.
If successful, zilebesiran could redefine the treatment paradigm for hypertension—offering patients and physicians a powerful, long-acting, and adherence-friendly therapeutic option.
Investor and Stakeholder Updates
Alnylam hosted an investor webcast on August 30, 2025, featuring company management and clinical experts including Dr. Neha Pagidipati and Professor Bryan Williams of University College London. The event provided an in-depth review of KARDIA-3 data and insights into the ZENITH trial design. A replay of the webcast is available in the Investors section of Alnylam’s website.
